CN1335769A - Controlled release formulation of divalproex sodium - Google Patents
Controlled release formulation of divalproex sodium Download PDFInfo
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- CN1335769A CN1335769A CN99814629A CN99814629A CN1335769A CN 1335769 A CN1335769 A CN 1335769A CN 99814629 A CN99814629 A CN 99814629A CN 99814629 A CN99814629 A CN 99814629A CN 1335769 A CN1335769 A CN 1335769A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
A controlled release tablet formulation which permits once daily dosing in the treatment of epilepsy comprises from about 50 weight percent to about 55 weight percent of an active ingredient selected from the group consisting of valproic acid, a pharmaceutically acceptable salt or ester of valproic acid, divalproex sodium, and valpromide; from about 20 weight percent to about 40 weight percent hydroxypropyl methylcellulose; from about 5 weight percent to about 15 weight percent lactose, from about 4 weight percent to about 6 weight percent microcrystalline cellulose, and from about 1 weight percent to about 5 weight percent silicon dioxide having an average particle size ranging between about 1 micron and about 10 microns; all weight percentages based upon the total weight of the tablet dosage form. Also disclosed are pre-tableting granular formulations, methods of making the granular formulations and tablets, and a method of treating epilepsy employing the controlled release tablet formulations of the invention.
Description
Technical field
The present invention relates to pharmaceutical preparation.More particularly, the present invention relates in controlled release tablet, contain the preparation of valproic acid, its officinal salt, ester or amide or divalproex sodium.
Background of invention
Be commonly referred to 2-Propylpentanoic, its amide valpromide (VPO) and some salt that should acid of valproic acid (VPA) and ester can be treated epilepsy effectively and as neuroleptics.The US4988731 of Meade discloses that to have mol ratio be oligomer 1: 1 and that contain 4 unitary sodium valproate and valproic acid.The US 5212326 of Meade discloses a kind of valproic acid of stable non-hygroscopic solid form, its comprise have mol ratio be 1: 1 and contain 4-6 unitary sodium valproate and valproic acid oligomer.Divalproex sodium (two valproic acid hydrogen sodium) is wherein a kind of current application Anti-epileptics the most widely.
Yet although can treat epilepsy effectively, certificate shows that the elimination half-life of valproic acid is shorter than other Anti-epileptics commonly used.It is reported that the half-life of this medicine is 6-17 hour in the adult, is 4-14 hour in the child.This causes the plasma concentration of medicine that sizable fluctuation, especially all the more so when long term administration is arranged.In order to keep moderately stable plasma concentration, just need frequently take medicine, this often makes the patient that the dosage regimen of prescription regulation is not too adapted to.In addition, the extensive fluctuation of this drug plasma concentration can make the amount of using in conservative dosage regimen be lower than the Drug therapy amount, and perhaps the amount of using in radical treatment is too high for particular patient.
In order to overcome this shortcoming, people have paid concerted effort and found can keep the Depakene of more constant medicine blood plasma level after administrations.The final goal of these researchs is to obtain stable blood plasma level in dosage regimen once a day.These effort generally belong to a class of following two apoplexy due to endogenous wind: find that (a) metabolism more lentamente can be by the preparation of timing or in check releasing mechanism release medicine to be discharged into intravital form of active ingredient and (b) to find.
The time-delay that people's such as Schor US 4369172 has for example described based on the mixture of hydroxypropyl emthylcellulose, ethyl cellulose and/or sodium carboxymethyl cellulose discharges therapeutic combination.This patentee has listed a lot of therapeutic agent that is incorporated in this preparation, comprises sodium valproate.
People's such as Friedman US 4913906 discloses and has comprised valproic acid, its amide or a kind of its salt or ester and natural or synthetic polymer, under high pressure suppresses controlled release form in blocks.
People's such as Brinker US 5009897 discloses and has been suitable for suppressing granule in blocks, and described granule comprises the coating of divalproex sodium nuclear core and polymer and microcrystalline cellulose mixt.
The US 5019398 of Daste discloses the continuous release tablet of divalproex sodium in hydroxypropyl emthylcellulose and hydrated SiO 2 substrate.
But people's such as Barry US 5055306 discloses effervescent or the water discrete particles extended release preparation that is applicable to multiple therapeutic agent.This granule comprises nuclear core and water-insoluble, the inflatable coating of water, and described nuclear core comprises active component and at least a excipient, and described coating comprises the copolymer and the water soluble hydroxy cellulose derivative of ethyl acrylate and methylmethacrylate.This patentee has listed a lot of therapeutic agent that can use in this invention preparation, comprise sodium valproate.
People's such as Brinkler US 5169642 discloses a kind of sustained release forms, wherein comprise the amide of divalproex sodium or valproic acid or the granule of ester, coating the sustained-release composition that contains ethyl cellulose or methylmethacrylate, plasticizer, antitack agent and slow release polymerization adhesion agent on the described granule.
People's such as Aubert US 5185159 discloses the preparation of valproic acid and sodium valproate, and said preparation does not use binding agent or granulation solvent to make.Said preparation is optional to comprise precipitated silica as antiplastering aid or antitack agent.
People's such as Exigua US 5589191 discloses the sodium valproate slow releasing tablet, and wherein this tablet coating the ethyl cellulose that contains silicic acid anhydride.
People's such as Ayer PCT application WO 94/27587 discloses the method for coming Taking Control of Epilepsy by the compositions of using valproic acid or derivatives thereof and poly-(alkylene oxide) bonded treatment.
People's such as Bialer ＂ Metabolism of Antiepileptic Drugs, ＂ pp.143-151, R.H.Levy.Ed..Raven Press, New York.1984; Int.J.Pharmaceutics.20:53-63 (1984); With Biopharmaceutics and Drug Disposition, 6:401-411 (1985); With Israel J.Med.Sci., 20:46-49 (1995) has reported the pharmacokinetics evaluation about several valproic acid extended release preparations.
Yet, still need effectively drug plasma concentration to be maintained the more valproic acid extended release preparation of constant level.
The invention summary
The present invention provides controlled release tablet in its main embodiment, wherein comprise the active component of the officinal salt that is selected from valproic acid, valproic acid or ester, divalproex sodium and the valpromide of about 55% weight of about 50%-; The hydroxypropyl emthylcellulose of about 40% weight of about 20%-; The lactose of about 15% weight of about 5%-, the microcrystalline Cellulose of about 6% weight of about 4%-, and the silicon dioxide of the mean diameter of about 5% weight of about 1%-between about 1 micron-Yue 10 microns; Wherein all wt percentage ratio all is by the gross weight of described tablet.
Described tablet provides the active medicine in hydrophilic matrix, this medicine release bioactive agent lentamente in the following manner in the time that prolongs: the mode that the drug plasma concentration of substantial constant level promptly is provided after administration once a day.
In another embodiment, the invention provides the dried particles compositions that is suitable for being pressed into tablet, this particulate composition comprises the granule of particle diameter less than about 1mm, and described granule comprises the active component of the officinal salt that is selected from valproic acid, valproic acid or ester, divalproex sodium and the valpromide of about 55% weight of about 50%-; The hydroxypropyl emthylcellulose of about 40% weight of about 20%-; The lactose of about 15% weight of about 5%-; The microcrystalline Cellulose of about 6% weight of about 4%-; And the silicon dioxide of the mean diameter of about 5% weight of about 1%-between about 1 micron-Yue 10 microns; Wherein all wt percentage ratio all is by the gross weight of described particulate composition.
In further embodiment, the invention provides the particulate composition that is suitable for being pressed into controlled release tablet, wherein said granule is to make by the method that comprises the steps: the mixture dry blending of the lactose of divalproex sodium that a) will about 55% weight of about 50%-, the hydroxypropyl emthylcellulose of about 40% weight of about 20%-and about 15% weight of about 5%-, to form the homogeneous mixture of dried ingredients; B) with step a) gained uniform drying mixture wet granulation; C) with step b) gained wet grain drying and screen particle diameter to select the granule of mean diameter less than 1mm; And d) with the microcrystalline Cellulose of gained granule and about 6% weight of about 4%-and the silicon dioxide dry blending of mean diameter between about 1 micron-Yue 10 microns of about 5% weight of about 1%-, perhaps microcrystalline Cellulose can mix with divalproex sodium, hydroxypropyl emthylcellulose and lactose in step (a).
In another embodiment, the invention provides the method for preparing the divalproex sodium controlled release tablet, comprising following step: the mixture dry blending of the lactose of divalproex sodium that a) will about 55% weight of about 50%-, the hydroxypropyl emthylcellulose of about 35% weight of about 20%-and about 15% weight of about 5%-, to form the homogeneous mixture of dried ingredients; B) with step a) gained uniform drying mixture wet granulation; C) with step b) gained wet grain drying and screen particle diameter to select the granule of mean diameter less than 1mm; D) with the microcrystalline Cellulose of gained granule and about 6% weight of about 4%-and the silicon dioxide dry blending of mean diameter between about 1 micron-Yue 10 microns of about 5% weight of about 1%-, with e) with step h) hybrid particles with about 2000 lbf (about 8.9 * 10
3Newton)-10000 lbf (about 4.45 * 10
4Newton) force compresses.In similar approach, microcrystalline Cellulose can be mixed with divalproex sodium, hydroxypropyl emthylcellulose and lactose in step (a).
The accompanying drawing summary
In the accompanying drawing that forms this description part: accompanying drawing 1 is to be illustrated in the figure that medicine discharges from the controlled release tablet of several tests under the conditions in vitro.Accompanying drawing 2 is figure that the expression medicine discharges from two kinds of preferred controlled release tablets of the present invention.What accompanying drawing 3 was represented is to use two kinds of intravital drug plasma concentrations of preferred controlled release tablet descendant of the present invention.What accompanying drawing 4 was represented is repeatedly to use the intravital valproic acid plasma concentration of preferred controlled release tablet descendant of the present invention.
Detailed Description Of The Invention
The term that is applied to pharmaceutical preparation in present specification and claims " continues to discharge ", " time-delay discharges " and " controlled release " has the PharmaceuticalSciences at ＂ Remington ' s, and ＂ 18
ThEd., p.1677, Mack Pub.Co., the implication of describing among the Easton, PA (1990) about them.Continue to discharge drug system and be included in any drug delivery system of realizing medicament slow release in time expand, and comprise that time-delay discharges and controlled release system.If this sustained release system can be kept the levels of drugs of substantial constant effectively in blood and target tissue, think that then it is a controlled release-drug delivery system.Yet, if drug delivery system can not successfully reach the blood of substantial constant or organize levels of drugs, but can prolong drug effect persistent period and surpass the conventional persistent period that is reached that discharges, think that it is the time-delay delivery system.
Preparation of the present invention provides the controlled release preparation of valproic acid.Term " valproic acid " thus comprise chemical compound 2-Propylpentanoic self and officinal salt and can be in vivo metabolism chemical compound for example valproic acid amide (valpromide) and other pharmaceutically acceptable amide and ester that should acid of generating valproic acid easily.For the present composition, particularly preferred valproic acid form is the complex that forms of one mole of 2-Propylpentanoic and its sodium salt-be commonly referred to " divalproex sodium ".Disclose divalproex sodium among the US 4988731 of Meade and the US 5212326, and by the following formula representative, wherein m is 2-about 6: experiment
Preparation contains 538mg divalproex sodium, magnesium stearate, dicalcium phosphate, microcrystalline Cellulose (Avicel
, FMC Corporation, Philadelphia, PA, USA) and/or lactose and different hydrophilic polymer 1 the gram tablet.The hydrophilic polymer of test comprises hydroxypropyl emthylcellulose, methylcellulose (Methocel
Level K100LVP CR, K4MP CR, K15MP CR and K 100MPCR, Dow Chemical, Midland, MI, USA); Hydroxypropyl cellulose (Klucel
LF, Hercules, Inc., Wilmington, DE, USA); And alginate (Keltone
Level LVCR and HVCR, Kelco Co., San Diego, CA, USA).
Before use, medicine is milled in batches, and crosses 40 mesh sieves (0.42mm nominal sieve aperture).With the batch medicine of milling and sieving and polymer and excipient in Collette Gral 10 high-shear mixers with the impeller speed dry blending of the high chopper speed of 3000rpm and 200rpm 5 minutes.By preparing granule with adding 70ml/kg granulation liquid (water or water/alcohol mixture) in this polymer of 1-2 branch clockwise/excipient powders mixture with the high chopper speed of 3000rpm and the impeller speed of 500rpm.Add 10-165ml liquid as required again to reach the granulation terminal point.Total granulation time is 2-18 minute.
The tablet matrix component comprises microcrystalline Cellulose, lactose, magnesium stearate and silicon dioxide.The gained granule is spent the night in 50 ℃ of-55 ℃ of tray dryings under reduced pressure.Dried granules is mixed with lubricant (magnesium stearate) in bag, cross 20 orders (0.84mm nominal sieve aperture) sieve then.In Model C Carver Press pelleter, use 0.747 inch (1.9cm) * 0.360 inch (0.91cm) load punch die with about 2000 lbf (about 8.9 * 10
3Newton)-Yue 10000 lbf (about 4.45 * 10
4Newton), preferred about 2300 lbf (1.02 * 10
4Newton)-Yue 5000 lbf (2.25 * 10
4Newton) tablet of the heavy 1g of compression stress compacting.The composition of this tablet is as shown in table 1.
Table 1
Test divalproex sodium substrate tablet
1Percentage by weight by the tablet total weight amount
1Poly-(vinylpyrrolidone) preliminary preparation screening
| Component 1 | A | ?B | ?C | ?D | ?E | ?F | ?G | ?H | ?I |
| Divalproex | 50 | ?50 | ?50 | ?50 | ?50 | ?53.8 | ?53.8 | ?53.8 | ?53.8 |
| Methocel K100LVPCR | 18 | ?20 | ?- | ?- | ?- | ?- | ?- | ?- | ?10 |
| Methocel K4MPCR | 8 | ?- | ?- | ?- | ?- | ?- | ?- | ?- | ?- |
| Klucel LF | - | ?20 | ?- | ?- | ?- | ?- | ?- | ?- | ?- |
| Keltone HVCR | - | ?- | ?30 | ?- | ?- | ?- | ?- | ?- | ?- |
| Methocel K15MPCR | - | ?- | ?- | ?- | ?30 | ?26 | ?35 | ?- | ?16 |
| Methocel K100MPCR | - | ?- | ?- | ?15 | ?- | ?- | ?- | ?30 | ?- |
| Lactose | 23 | ?9.5 | ?9.5 | ?29.5 | ?14.5 | ?14.7 | ?5.7 | ?10.7 | ?14.7 |
| Avicel PH101 | - | ?0 | ?5 | ?5 | ?5 | ?5 | ?5 | ?5 | ?5 |
| PVP 2 | - | ?- | ?5 | ?- | ?- | ?- | ?- | ?- | ?- |
| Magnesium stearate | 1 | ?0.5 | ?0.5 | ?0.5 | ?0.5 | ?0.5 | ?0.5 | ?0.5 | ?0.5 |
Carry out the Preliminary screening of substrate tablet with a plurality of experiments.With the tablet hardness of the various preparations of Model VK2000 VanKel tablet hardness analysis-e/or determining, and be unit as the meansigma methods record of 10 tests with kPa (kP).
By the rotation of tablet sample being come the fragility of test tablet for 100 times with Erweka TA fragility analyzer.Damage the tablet fragility of calculating various preparations according to the weight of tablet in this test.
By graduated glass cylinder is filled to the bulk density that the 100ml labelling is measured preparation granules carefully.Measure tap density after the graduated cylinder of filling touched 100 times.
Mensuration particle grain size distribution as described below: collect and assess fine particle and oarse-grained percentage ratio greater than 140 orders (about 0.105mm nominal sieve aperture) and 40 orders (about 0.42mm nominal sieve aperture).
Be used in the device II that describes among the American Pharmacopeia XXI/ NF XVI and carry out the dissolution in vitro test.Get the 1.5ml aliquot and, pass through TDX via the filtration of 0.45 μ m filter
Fluorescence polarization immunoassay is measured.After each sampling, in the test mixing thing, add isopyknic medium to keep constant volume.Test condition is as follows: device USP II, oar formula medium 1M HCl (a hour): the remaining time is 0,0.5,1,2,4,6,8,13,24 hour sample time of 37 ℃ ± 0.5 ℃ oar speed 100rpm of pH6.8 buffer solution medium volume 900ml temperature sample volume 1.5ml
The result of these tests is as shown in table 2.
According to the data in these preliminary experiments and the table 2, drawn following conclusion: (1) is to the influence of tablet hardness: use ethanol often can improve tablet hardness as granulation liquid.Between the particle diameter of ethanol and batch medicine very strong interaction is arranged.Only in the preparation that contains the greater particle size medicine, observed the hardness increase.The observed drug less for particle diameter arrived adverse effect.(2) to brittle influence: use medicine to reduce fragility with small particle diameter.Yet this effect only is significant in the preparation that makes water as granulation liquid.(3) to the influence of density: the result shows, uses ethanol to reduce particulate density as granulation liquid.Yet, observed ethanol and used Klucel
, and ethanol and diameter of aspirin particle between remarkable interaction.Ethanol has only reduced the preparation that contains the greater particle size medicine and/or has not contained Klucel
The density of preparation.For containing less drug particles and/or Klucel
Preparation, observed adverse effect.To bulk density or tap density, obtained same conclusions.(4) to the influence of granular size: use medicine to obtain the bigger granule of more particle diameter with greater particle size.In addition, ethanol and Klucel
Between interaction be significant, promptly in preparation, do not have Klucel
The time use ethanol often can produce larger particles.For containing 4%Klucel
Preparation then do not observe any effect.There is the factor of appreciable impact to comprise ethanol, diameter of aspirin particle and the interaction between them to fine particle percentage ratio in the granule.Use less drug particles often can make more fine particle is arranged in the granule.When using ethanol, produced more fine particle as granulation liquid.Alcoholic acid effect is the most remarkable to the preparation that contains the small particle diameter medicine.(5) to the influence of granulation liquid volume:, contain less grainsize medicine or use ethanol as the bigger liquid volume of the preparation needs of granulation liquid in order to reach the granulation terminal point.(6) vitro drug release: the percentage of valproic acid from controlled release tablet discharges as shown in Figure 1 under conditions in vitro.Release characteristic difference between preparation is very little.In this experiment, use release percentage ratio (Q at the 8th hour
8hr) represent rate of release to carry out data analysis.Found that, in preparation, use Klucel
Or the medicine of greater particle size causes rate of release to increase.When using Q
10hrOr Q
24hrObtained similar results when estimating rate of release.
The preparation that contains high load capacity and high-viscosity polymer often shows the compressibility of going on business.It is believed that this is because along with due to polymer ordered property of the increase of molecular weight and the elasticity increase.At about 3000 lb (1.3 * 10
4Newton)-Yue 10000 lb (4.45 * 10
4Newton) under the compression stress, the hardness of tablet almost remains unchanged.
Table 2
1Be defined as particulate percentages by 0.105mm nominal sieve aperture
2Be defined as the percent of drug that discharges in during 8 hours under the testing in vitro condition
| Preparation | The granulation liquid volume | Hardness (kP) | Fragility (% loss) | Tap density (g/ml) | Bulk density (g/ml) | % particle diameter＞40 orders | Fine particle | ???Q 8hr(％) 2 |
| ????A | ????100 | ????11.9 | ?0.049 | ?0.504 | ?0.429 | ????22.6 | ?6.1 | ????27.6 |
| ????B | ????80 | ????7.2 | ?0.16 | ?0.515 | ?0.438 | ????31.3 | ?9.8 | ????29.0 |
| ????C | ????115 | ????12.2 | ?0.025 | ?0.459 | ?0.39 | ????30.2 | ?3.3 | ????28.6 |
| ????D | ????80 | ????8.4 | ?0.162 | ?0.459 | ?0.406 | ????38.2 | ?6.6 | ????30.4 |
| ????E | ????235 | ????10.4 | ?0.060 | ?0.599 | ?0.509 | ????21.5 | ?40.7 | ????27.0 |
| ????F | ????110 | ????12.2 | ?0.006 | ?0.400 | ?0.340 | ????49.2 | ?1.8 | ????28.0 |
| ????G | ????200 | ?????9.4 | ?0.085 | ?0.596 | ?0.506 | ?????24.0 | ?29.7 | ????29.7 |
| ????H | ????150 | ?????12.9 | ?0.142 | ?0.593 | ?0.504 | ?????35.0 | ?22.8 | ????30.0 |
| ????I | ????130 | ?????9.5 | ?0.015 | ?0.475 | ?0.404 | ?????33.8 | ?1.2 | ????28.8 |
In order to improve tablet hardness, to granule, add a small amount of microcrystalline Cellulose from the outside and colloidal silica is tested by level with 1-5%.Table 3 has shown test result.Found that, add a small amount of microcrystalline Cellulose or colloidal silica and significantly improved tablet hardness.
Table 3
The influence that adds microcrystalline Cellulose or silicon dioxide from the outside
1Silicon dioxide be mean diameter be the 0.2-0.3 micron Cab-O-Sil M-5 sootiness silicon dioxide (Cabot Corp., Boyertown, PA, USA).
| The hardness test preparation | Additive | Hardness (kP) |
| ????Ia | Do not have | ????6.2 |
| ????Ib | ?5％Avicel | ????9.6 |
| ????Ic | ?5％Avicel With 1% silicon dioxide 1 | ????13.8 |
| ????IIa | Do not have | ????- |
| ????IIb | 1% silicon dioxide 1 | ????10.9 |
| ????IIc | ?5％Avicel With 1% silicon dioxide 1 | ????14.4 |
| ????IIIa | Do not have | ????5.8 |
| ????IIIb | 1% silicon dioxide 1 | ????10.8 |
| ????IIIc | ?5％Avicel With 1% silicon dioxide 1 | ????14.8 |
Shown in the data in the table 3, adding 1% silicon dioxide or 5% microcrystalline Cellulose almost make tablet hardness increase by one times in hydrophilic matrix preparation of the present invention, and both's adding makes tablet hardness increase more than one times.Yet, though The above results has confirmed to unite the Avicel that use adds
Microcrystalline Cellulose and Cab-O-sil
Silicon dioxide can improve tablet hardness, but still has cohesiveness and lower density issue.Small particle diameter Cab-O-Sil
The low bulk density of sootiness silicon dioxide (being 40g/l) has brought the problem that the capacity material can not be loaded on the tablet die.
In order to address this problem, use mean diameter to be about 1 micron-Yue 10 microns, preferred about 2 microns-Yue 5 microns, the different silicon dioxide of 2-3 micron most preferably from about.Wherein a kind of spendable such material is available from W.R.Grace, Lexington, MA, the Syloid of USA
244.When using this material, be antitack agent and the sclerosing agent of wanting used as film-making at first, but brought wondrous and unforeseeable advantage as follows to preparation.This material is that " from the outside " is added in (adding) preparation: that is to say, and with active component, polymer and excipient dry blending, wet granulation, dry then and screen particle diameter.Afterwards silicon dioxide is added in the granular preparation, and the gained mixture is mixed, compacting in flakes then.
According to The above results, absorption experiment is selected preferred tablet in the body that carries out in the health volunteer.The component of preparation and extracorporeal releasing speed are respectively shown in table 4 and accompanying drawing 2.Mix by independent use high viscosity HPMC or with low viscosity HPMC and to design preparation with different rate of release.The select target extracorporeal releasing speed is so that medicine discharges 16-20 hour in vivo.
Two kinds of preferred formulations that use is described in table 4 carry out experiment in 2 individualities in the experimenter.Accompanying drawing 3 has shown valproic acid mean plasma concentration-time relationship in vivo behind oral once these two kinds of preparations.Found that preferred preparation A and B provide the time-delay absorption of the valproic acid of about 10 hours and 24 hours respectively.Therefrom can obviously find out, discharge slower preparation-tablet B and show preferable lasting blood plasma level.Therefore, further test said preparation in the multidose experiment, this experiment is carried out in the health volunteer, is administered once every day with about 1 oral dose that restrains.Result as shown in Figure 4 shows that the average steady state blood plasma level is well controlled the g/ml at 62.3-78.2 μ, and has atomic little fluctuation, and this level drops on the therapeutic domain interior (30-100 μ g/ml) of valproic acid.
Table 4
Preferred controlled release preparation of the present invention
1Medicine is crossed 40 mesh sieves (0.42mm nominal sieve aperture) in batches
2All percentage ratios in the table all are the percentage by weights by the gross weight of tablet
| Component | Preferred preparation A | Preferred preparation B |
| Divalproex sodium (milling) 1 | ????53.82％ 2 | ????53.82％ |
| Hydroxypropyl emthylcellulose (Methocel K15M.CR) | ????8％ | ????30％ |
| Methylcellulose (Methocel K100L.CR) | ????18％ | ????- |
| Lactis Anhydrous | ????12.18％ | ????8.18％ |
| Microcrystalline Cellulose (Avicel PH101) | ????5％ | ????5％ |
| Silicon dioxide (mean diameter 1 μ m＜＞10 μ m) (Syloid 244) | ????3％ | ????3％ |
| The tablet total weight amount | ????1g | ????1g |
Therefore, controlled release tablet of the present invention provides the effective delivery system that is used for the patient of needs treatment is used in mode once a day valproic acid (divalproex sodium).Preparation of the present invention provides the valproic acid plasma concentration of substantial constant level, and this concentration drops in the therapeutic domain of this medicine in during allowing to be administered once every day.
Though shown and described the preferred embodiment of the invention, field of pharmaceutical preparations technical staff should be appreciated that and can do various changes to preparation and method under the preceding topic that does not deviate from the scope of the invention that is defined by the claims.
Claims (15)
1. controlled release tablet wherein comprises
A) active component of the officinal salt that is selected from valproic acid, valproic acid of about 55% weight of about 50%-or ester, divalproex sodium and valpromide;
B) hydroxypropyl emthylcellulose of about 40% weight of about 20%-;
C) lactose of about 15% weight of about 5%-, the microcrystalline Cellulose of about 6% weight of about 4%-, and the silicon dioxide of the mean diameter of about 5% weight of about 1%-between about 1 micron-Yue 10 microns; Wherein all wt percentage ratio all is by the gross weight of described tablet.
2. the controlled release tablet of claim 1, wherein said active component is a divalproex sodium.
3. the controlled release tablet of claim 1, wherein by the gross weight of tablet, the content of described hydroxypropyl emthylcellulose is about 40% weight of about 20%-.
4. the controlled release tablet of claim 1, the mean diameter of wherein said silicon dioxide is between about 2 microns-Yue 5 microns.
5. controlled release tablet wherein comprises the microcrystalline Cellulose of the lactose of the hydroxypropyl emthylcellulose of the divalproex sodium of about 54% weight, about 30% weight, about 8% weight, about 5% weight and the silicon dioxide of mean diameter between 2 microns-5 microns of about 3% weight.
6. be used to be pressed into the particulate composition of controlled release tablet, the particle diameter of described particulate composition and comprises between the about 0.84mm of about 0.100mm-
A) active component of the officinal salt that is selected from valproic acid, valproic acid of about 55% weight of about 50%-or ester, divalproex sodium and valpromide;
B) hydroxypropyl emthylcellulose of about 35% weight of about 20%-;
C) lactose of about 15% weight of about 5%-;
D) microcrystalline Cellulose of about 6% weight of about 4%-; With
E) silicon dioxide of the mean diameter of about 5% weight of about 1%-between about 1 micron-Yue 10 microns;
Wherein all wt percentage ratio all is by the gross weight of described particulate composition.
7. the particulate composition of claim 6, wherein said active component is a divalproex sodium.
8. the particulate composition of claim 7, wherein by the gross weight of tablet, the content of described hydroxypropyl emthylcellulose is about 40% weight of about 25%-.
9. the particulate composition of claim 7, the mean diameter of wherein said silicon dioxide is between about 2 microns-Yue 5 microns.
10. be used to be pressed into the particulate composition of controlled release tablet, wherein comprise the microcrystalline Cellulose of the lactose of the hydroxypropyl emthylcellulose of the divalproex sodium of about 54% weight, about 30% weight, about 8% weight, about 5% weight and the silicon dioxide of mean diameter between 2 microns-5 microns of about 3% weight.
11. preparation is suitable for being pressed into the method for the particulate composition of controlled release tablet, comprising following step:
The mixture dry blending of the lactose of divalproex sodium that a) will about 55% weight of about 50%-, the hydroxypropyl emthylcellulose of about 40% weight of about 20%-and about 15% weight of about 5%-is to form the homogeneous mixture of dried ingredients;
B) with step a) gained uniform drying mixture wet granulation;
C) step b) gained wet grain drying is also sieved to select the granule of mean diameter less than about 0.84mm; With
D) do the microcrystalline Cellulose of gained granule and about 6% weight of about 4%-and the silicon dioxide of mean diameter between about 1 micron-Yue 10 microns of about 5% weight of about 1%-mixed.
12. prepare the method for divalproex sodium controlled release tablet, comprising following step:
A) divalproex sodium is milled in batches, and screening is to obtain the divalproex sodium of mean diameter less than about 0.5mm;
The mixture dry blending of the lactose of divalproex sodium that b) will about 55% weight of about 50%-, the hydroxypropyl emthylcellulose of about 35% weight of about 20%-and about 15% weight of about 5%-is to form the homogeneous mixture of dried ingredients;
C) with step a) gained uniform drying mixture wet granulation;
D) step b) gained wet grain drying is also sieved to select the granule of mean diameter less than 1mm;
E) with the microcrystalline Cellulose of gained granule and about 6% weight of about 4%-and the silicon dioxide dry blending of mean diameter between about 1 micron-Yue 10 microns of about 5% weight of about 1%-; With
F) with step h) hybrid particles with about 2000 lbf (about 8.9 * 10
3Newton)-10000 lbf (about 4.45 * 10
4Newton) force compresses.
13. the method for claim 12, the mean diameter of wherein said silicon dioxide is between about 2 microns-5 microns.
14. the method for treatment epilepsy comprises that the patient to this treatment of needs uses controlled release tablet in mode once a day, described controlled release tablet comprises the divalproex sodium of day therapeutic dose in substrate, and described substrate comprises:
A) hydroxypropyl emthylcellulose of about 40% weight of about 20%-;
B) lactose of about 15% weight of about 5%-;
C) microcrystalline Cellulose of about 6% weight of about 4%-; With
D) silicon dioxide of the mean diameter of about 5% weight of about 1%-between about 1 micron-Yue 10 microns;
Wherein all wt percentage ratio all is by the gross weight of described tablet.
15. the method for claim 14, the mean diameter of wherein said silicon dioxide is between about 2 microns-5 microns.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/216,650 | 1998-12-18 | ||
| US09/216,650 US6419953B1 (en) | 1998-12-18 | 1998-12-18 | Controlled release formulation of divalproex sodium |
| US12155799P | 1999-02-25 | 1999-02-25 | |
| US60/121,557 | 1999-02-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1335769A true CN1335769A (en) | 2002-02-13 |
Family
ID=26819594
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99814629A Pending CN1335769A (en) | 1998-12-18 | 1999-12-09 | Controlled release formulation of divalproex sodium |
Country Status (25)
| Country | Link |
|---|---|
| EP (1) | EP1140034B1 (en) |
| JP (1) | JP2003513882A (en) |
| KR (1) | KR20010101295A (en) |
| CN (1) | CN1335769A (en) |
| AR (1) | AR021443A1 (en) |
| AT (1) | ATE254907T1 (en) |
| AU (1) | AU2478900A (en) |
| BG (1) | BG105665A (en) |
| BR (1) | BR9916361A (en) |
| CA (1) | CA2330480C (en) |
| CO (1) | CO5160287A1 (en) |
| CZ (1) | CZ20012201A3 (en) |
| DE (1) | DE69913197T2 (en) |
| DK (1) | DK1140034T3 (en) |
| ES (1) | ES2212667T3 (en) |
| HK (1) | HK1043043B (en) |
| HU (1) | HUP0105463A3 (en) |
| IL (1) | IL143407A0 (en) |
| NO (1) | NO20012986L (en) |
| PL (1) | PL356899A1 (en) |
| PT (1) | PT1140034E (en) |
| SI (1) | SI20624A (en) |
| SK (1) | SK8252001A3 (en) |
| TW (1) | TW585788B (en) |
| WO (1) | WO2000037055A1 (en) |
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| CN102138911A (en) * | 2011-03-28 | 2011-08-03 | 孙卫东 | Divalproex sodium sustained release tablets and preparation method thereof |
| CN102421428A (en) * | 2009-05-12 | 2012-04-18 | 株式会社爱茉莉太平洋 | Composition for preventing hair loss or for stimulating hair growth |
| CN102895201A (en) * | 2011-07-26 | 2013-01-30 | 北大方正集团有限公司 | Valproate semisodium tablet and its preparation method |
| CN105012264A (en) * | 2014-04-16 | 2015-11-04 | 四川科瑞德制药有限公司 | Sodium valproate sustained release tablet as well as preparation process and application thereof |
| CN106389368A (en) * | 2015-07-29 | 2017-02-15 | 四川科瑞德制药股份有限公司 | Sodium valproate sustained release preparation as well as preparation process and applications thereof |
| CN107028907A (en) * | 2016-02-04 | 2017-08-11 | 成都康弘药业集团股份有限公司 | A kind of Divalproex sodium sustained-release tablet |
| CN114681419A (en) * | 2020-12-28 | 2022-07-01 | 湖南省湘中制药有限公司 | Composition of valproamide sustained-release tablets and preparation method thereof |
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| US6528090B2 (en) | 1998-12-18 | 2003-03-04 | Abbott Laboratories | Controlled release formulation of divalproex sodium |
| US6419953B1 (en) | 1998-12-18 | 2002-07-16 | Abbott Laboratories | Controlled release formulation of divalproex sodium |
| US6713086B2 (en) | 1998-12-18 | 2004-03-30 | Abbott Laboratories | Controlled release formulation of divalproex sodium |
| US20020025341A1 (en) * | 1998-12-18 | 2002-02-28 | Yihong Qiu | Controlled release formulation of divalproex sodium |
| US6511678B2 (en) | 1998-12-18 | 2003-01-28 | Abbott Laboratories | Controlled release formulation of divalproex sodium |
| WO2002051402A1 (en) * | 2000-12-22 | 2002-07-04 | Abbott Laboratories | Controlled release formulation of divalproex sodium |
| KR100911779B1 (en) * | 2001-05-25 | 2009-08-12 | 세파론, 인코포레이티드 | Solid Pharmaceutical Formulations Comprising Modafinil |
| US7229644B2 (en) * | 2002-05-23 | 2007-06-12 | Cephalon, Inc. | Pharmaceutical formulations of modafinil |
| US20040005357A1 (en) * | 2002-07-03 | 2004-01-08 | Sherman Bernard Charles | Extended-release tablets comprising divalproex sodium |
| US20040048931A1 (en) | 2002-07-12 | 2004-03-11 | Craig Heacock | Modafinil pharmaceutical compositions |
| US20040116532A1 (en) | 2002-09-13 | 2004-06-17 | Craig Heacock | Pharmaceutical formulations of modafinil |
| EP1603540A2 (en) * | 2003-03-14 | 2005-12-14 | Nirmal Mulye | A process for preparing sustained release tablets |
| HUP0301537A3 (en) * | 2003-06-03 | 2005-07-28 | Egis Gyogyszergyar Nyilvanosan | Deramcyclane fumarate tablets and process for producing them |
| US7713550B2 (en) | 2004-06-15 | 2010-05-11 | Andrx Corporation | Controlled release sodium valproate formulation |
| WO2006025029A2 (en) * | 2004-08-31 | 2006-03-09 | Ranbaxy Laboratories Limited | Extended release composition of divalproex |
| BRPI0606932A2 (en) * | 2005-01-26 | 2009-07-28 | Elan Pharma Int Ltd | formulation, dosage form, and use of a therapeutically effective amount of a formulation |
| US20070202164A1 (en) * | 2006-02-28 | 2007-08-30 | Hutchison Medipharma Enterprises Limited | Andrographis Extract Formulations |
| WO2012121862A2 (en) * | 2011-02-17 | 2012-09-13 | University Of Florida Research Foundation | Valproic acid derivative compounds |
| EP2919903B1 (en) | 2012-11-14 | 2020-07-22 | W.R. Grace & CO. - CONN. | Compositions containing a biologically active material and a non-ordered inorganic oxide |
| CN105456218A (en) * | 2015-12-07 | 2016-04-06 | 黑龙江省智诚医药科技有限公司 | Magnesium valproate sustained-release tablet and preparing method thereof |
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| US5169642A (en) * | 1988-06-24 | 1992-12-08 | Abbott Laboratories | Sustained-release drug dosage units |
| US5009897A (en) * | 1988-06-24 | 1991-04-23 | Abbott Laboratories | Pharmaceutical granules and tablets made therefrom |
| FR2643556B1 (en) * | 1989-02-27 | 1993-03-05 | Sanofi Sa | PHARMACEUTICAL COMPOSITION WITH SUSTAINED RELEASE OF VALPROIC ACID |
| IL96311A (en) * | 1989-12-01 | 1995-05-26 | Abbott Lab | Sustained-release drug dosage units |
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-
1999
- 1999-12-09 EP EP99968104A patent/EP1140034B1/en not_active Expired - Lifetime
- 1999-12-09 SK SK825-2001A patent/SK8252001A3/en unknown
- 1999-12-09 HU HU0105463A patent/HUP0105463A3/en unknown
- 1999-12-09 SI SI9920100A patent/SI20624A/en not_active IP Right Cessation
- 1999-12-09 AT AT99968104T patent/ATE254907T1/en active
- 1999-12-09 PT PT99968104T patent/PT1140034E/en unknown
- 1999-12-09 BR BR9916361-6A patent/BR9916361A/en not_active Application Discontinuation
- 1999-12-09 CZ CZ20012201A patent/CZ20012201A3/en unknown
- 1999-12-09 KR KR1020017007649A patent/KR20010101295A/en not_active Application Discontinuation
- 1999-12-09 IL IL14340799A patent/IL143407A0/en unknown
- 1999-12-09 DE DE69913197T patent/DE69913197T2/en not_active Expired - Lifetime
- 1999-12-09 JP JP2000589166A patent/JP2003513882A/en active Pending
- 1999-12-09 ES ES99968104T patent/ES2212667T3/en not_active Expired - Lifetime
- 1999-12-09 PL PL99356899A patent/PL356899A1/en not_active Application Discontinuation
- 1999-12-09 WO PCT/US1999/029204 patent/WO2000037055A1/en not_active Application Discontinuation
- 1999-12-09 CN CN99814629A patent/CN1335769A/en active Pending
- 1999-12-09 CA CA002330480A patent/CA2330480C/en not_active Expired - Fee Related
- 1999-12-09 AU AU24789/00A patent/AU2478900A/en not_active Abandoned
- 1999-12-09 DK DK99968104T patent/DK1140034T3/en active
- 1999-12-15 CO CO99078240A patent/CO5160287A1/en unknown
- 1999-12-17 AR ARP990106552A patent/AR021443A1/en not_active Application Discontinuation
- 1999-12-18 TW TW088122338A patent/TW585788B/en not_active IP Right Cessation
-
2001
- 2001-06-15 NO NO20012986A patent/NO20012986L/en not_active Application Discontinuation
- 2001-07-03 BG BG105665A patent/BG105665A/en unknown
-
2002
- 2002-03-28 HK HK02102407.1A patent/HK1043043B/en not_active IP Right Cessation
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102421428A (en) * | 2009-05-12 | 2012-04-18 | 株式会社爱茉莉太平洋 | Composition for preventing hair loss or for stimulating hair growth |
| CN102138911A (en) * | 2011-03-28 | 2011-08-03 | 孙卫东 | Divalproex sodium sustained release tablets and preparation method thereof |
| CN102138911B (en) * | 2011-03-28 | 2012-12-12 | 孙卫东 | Divalproex sodium sustained release tablets and preparation method thereof |
| CN102895201A (en) * | 2011-07-26 | 2013-01-30 | 北大方正集团有限公司 | Valproate semisodium tablet and its preparation method |
| CN102895201B (en) * | 2011-07-26 | 2014-09-10 | 北大方正集团有限公司 | Valproate semisodium tablet and its preparation method |
| CN105012264A (en) * | 2014-04-16 | 2015-11-04 | 四川科瑞德制药有限公司 | Sodium valproate sustained release tablet as well as preparation process and application thereof |
| CN105012264B (en) * | 2014-04-16 | 2019-11-29 | 四川科瑞德制药股份有限公司 | Sustained-release Sodium Valproate and its preparation process and purposes |
| CN106389368A (en) * | 2015-07-29 | 2017-02-15 | 四川科瑞德制药股份有限公司 | Sodium valproate sustained release preparation as well as preparation process and applications thereof |
| CN107028907A (en) * | 2016-02-04 | 2017-08-11 | 成都康弘药业集团股份有限公司 | A kind of Divalproex sodium sustained-release tablet |
| CN114681419A (en) * | 2020-12-28 | 2022-07-01 | 湖南省湘中制药有限公司 | Composition of valproamide sustained-release tablets and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2330480A1 (en) | 2000-06-29 |
| CZ20012201A3 (en) | 2001-09-12 |
| DK1140034T3 (en) | 2004-03-08 |
| HK1043043A1 (en) | 2002-09-06 |
| WO2000037055A1 (en) | 2000-06-29 |
| DE69913197T2 (en) | 2004-09-02 |
| PL356899A1 (en) | 2004-07-12 |
| TW585788B (en) | 2004-05-01 |
| NO20012986L (en) | 2001-08-15 |
| JP2003513882A (en) | 2003-04-15 |
| NO20012986D0 (en) | 2001-06-15 |
| BG105665A (en) | 2002-03-29 |
| EP1140034B1 (en) | 2003-11-26 |
| CO5160287A1 (en) | 2002-05-30 |
| SI20624A (en) | 2002-02-28 |
| KR20010101295A (en) | 2001-11-14 |
| HUP0105463A2 (en) | 2002-05-29 |
| PT1140034E (en) | 2004-03-31 |
| DE69913197D1 (en) | 2004-01-08 |
| HK1043043B (en) | 2004-09-10 |
| ATE254907T1 (en) | 2003-12-15 |
| SK8252001A3 (en) | 2001-12-03 |
| ES2212667T3 (en) | 2004-07-16 |
| EP1140034A1 (en) | 2001-10-10 |
| AU2478900A (en) | 2000-07-12 |
| CA2330480C (en) | 2002-05-21 |
| BR9916361A (en) | 2002-11-05 |
| AR021443A1 (en) | 2002-07-17 |
| IL143407A0 (en) | 2002-04-21 |
| HUP0105463A3 (en) | 2003-03-28 |
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